Mono- and multimeric PSMA-targeting small molecule-thorium-227 conjugates for optimized efficacy and biodistribution...

Area of Science:

• Radiopharmaceutical chemistry
• Oncology
• Molecular imaging and therapy

Background:

• Prostate-specific membrane antigen (PSMA) is a key biomarker for prostate cancer (PrCa).
• PSMA-targeting conjugates like PSMA-617 are clinically used for PrCa treatment, often with radionuclides like lutetium-177 or actinium-225.
• There is a need for PSMA-targeting agents that can be efficiently labeled with alpha emitters like thorium-227 for enhanced therapeutic potential.

Purpose of the Study:

• To develop novel PSMA-targeting small molecule (SMOL) conjugates for efficient labeling with thorium-227.
• To create conjugates with high uptake in PSMA-expressing tumors and rapid systemic clearance.
• To evaluate the therapeutic potential of these novel PSMA-targeting thorium conjugates (SMOL-TTCs).

Main Methods:

• Developed a novel linker motif and a hydrophilic 2,3-hydroxypyridinone chelator (carboxy-HOPO) for robust thorium-227 labeling.
• Synthesized monomeric and multimeric PSMA SMOL conjugates (PSMA SMOL-TTCs).
• Assessed in vitro binding, internalization, antiproliferative activity, and in vivo antitumor efficacy and biodistribution in preclinical models.

Main Results:

• PSMA SMOL-TTCs were readily labeled with thorium-227, exhibiting high stability and potent in vitro activity.
• In vivo studies showed fast clearance, significant antitumor efficacy, and high uptake/retention in prostate tumors in mice.
• Minimal off-target organ uptake (except kidneys) and stable thorium-227 complexation were observed.

Conclusions:

• Monomeric and multimeric PSMA SMOL-TTCs demonstrate promising high tumor uptake and fast clearance in preclinical settings.
• These novel thorium-227-labeled conjugates represent a potential new therapeutic strategy for prostate cancer.
• Further therapeutic exploration of PSMA SMOL-TTCs is warranted.